AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity

Blair Jessica M. A.; Bavro Vassiliy N.; Ricci VitoModi NirajCacciotto PierpaoloKleinekathoefer UlrichRuggerone PaoloVargiu Attilio V.Baylay Alison J.Smith Helen E.Brandon YvonneGalloway DavidPiddock Laura J. V.

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AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity

机译：AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity

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The incidence of multidrug-resistant bacterial infections is increasing globally and the need to understand the underlying mechanisms is paramount to discover new therapeutics. The efflux pumps of Gram-negative bacteria have a broad substrate range and transport antibiotics out of the bacterium, conferring intrinsic multidrug resistance (MDR). The genomes of pre- and posttherapy MDR clinical isolates of Salmonella Typhimurium from a patient that failed antibacterial therapy and died were sequenced. In the posttherapy isolate we identified a novel G288D substitution in AcrB, the resistance-nodulation division transporter in the AcrAB-ToIC tripartite MDR efflux pump system. Computational structural analysis suggested that G288D in AcrB heavily affects the structure, dynamics, and hydration properties of the distal binding pocket altering specificity for antibacterial drugs. Consistent with this hypothesis, recreation of the mutation in standard Escherichia coli and Salmonella strains showed that G288D AcrB altered substrate specificity, conferring decreased susceptibility to the fluoroquinolone antibiotic ciprofloxacin by increased efflux. At the same time, the substitution increased susceptibility to other drugs by decreased efflux. Information about drug transport is vital for the discovery of new antibacterials; the finding that one amino acid change can cause resistance to some drugs, while conferring increased susceptibility to others, could provide a basis for new drug development and treatment strategies.

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《Proceedings of the National Academy of Sciences of the United States of America》 |2015年第11期|3511-3516|共6页
作者
Blair Jessica M. A.; Bavro Vassiliy N.; Ricci VitoModi NirajCacciotto PierpaoloKleinekathoefer UlrichRuggerone PaoloVargiu Attilio V.Baylay Alison J.Smith Helen E.Brandon YvonneGalloway DavidPiddock Laura J. V.;
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作者单位

Univ Birmingham, Inst Microbiol & Infect, Coll Med & Dent Sci, Antimicrobials Res Grp,Sch Immun & Infect, Birmingham B15 2TT, W Midlands, England;

Jacobs Univ Bremen, Sch Engn & Sci, D-28759 Bremen, Germany;

Univ Cagliari, Dept Phys, I-09042 Monserrato, Italy;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
efflux; antimicrobial resistance; AcrB; whole genome sequencing;

AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity

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